Plasticity in the striatum supports habit and goal-directed learning, and aberrant plasticity contributes to addiction and substance abuse. The principle cells of the striatum?spiny projection neurons (SPNs)? integrate cortical, thalamic, dopaminergic, and local inhibitory inputs. Dorsomedial striatum (DMS) receives input from associative cortex to mediate goal-directed learning, and dorsolateral striatum (DLS) receives input from sensorimotor cortex to mediate habit learning. Plasticity in both regions requires intracellular calcium elevation. The magnitude, duration, and location of calcium influx is hypothesized to determine the outcome of synaptic plasticity, consistent with in vitro brain slice experiments. Most striatal plasticity findings are from in vitro experiments conducted with regular, repeated inputs. It is unclear how in vivo-like inputs affect calcium dynamics and synaptic plasticity, limiting the applicability of ex vivo plasticity findings to in vivo conditions. Therefore, the overarching goal here is to integrate ex vivo mechanisms with in vivo-like conditions to determine plasticity outcomes in response to cortical activity. Further, this project will determine contributions of intrinsic cellular mechanisms and network activity to observed differences in DMS and DLS plasticity. To translate in vitro plasticity findings to in vivo like conditions, experimentally-constrained computational models of SPNs will be developed and morphological reconstruction experiments conducted to investigate effects of synaptic activity patterns on plasticity. Simulation experiments will evaluate the central hypothesis that in vivo-like patterns of synaptic input will support striatal synaptic plasticity by addressing the following aims. Aim 1: Test the hypothesis that spatiotemporal patterns of synaptic input will produce nonlinear spatially specific spine calcium. Multiple synaptic inputs placed with spatially clustered or distributed patterns and activated with temporal variability will be simulated and their effects on spine calcium dynamics evaluated to delineate rules governing control of calcium dynamics. Aim 2: Test the hypothesis that in vivo- like patterns of synaptic input will produce consistent calcium elevations and synaptic plasticity in a subset of spines. In vivo-like input patterns will be constructed from cortical spike trains and simulated with various degrees of trial-to-trial variability to identify the sensitivity of plasticity to variable cortical inputs during repeated trials. Aim 3: Determine whether differences in dorsomedial and dorsolateral plasticity depend on intrinsic cellular differences or differences in presynaptic activity. Cell-type specific models of dorsomedial and dorsolateral SPNs will be developed from morphological reconstruction of neurons to determine whether differences in plasticity underlying goal-directed versus habit learning depend on intrinsic cellular properties, morphology, and/or synaptic inputs. The proposed research will yield key insights into in vivo like conditions that induce plasticity in habit and goal directed learning. These findings may guide future research into targets for therapeutic intervention in addiction.